PROJECT SUMMARY Chagas cardiomyopathy is still a leading cause of death in Latin American countries. It is also an emerging infectious disease in the US, estimated to have approximately 300,000 individuals with Chagas disease living within its borders. One of the most important and still unanswered questions in the disease is why only 30% of infected individuals develop chronic forms of end-stage cardiomyopathy. Here we hypothesize that genetic susceptibility is paramount and modulates end-stage disease development. For testing this hypothesis we will use a genetics approach based on the investigation of common genetic variation that may associate with disease development. In parallel, we will build the tools to also investigate whether rare genetic variations also have a role in disease susceptibility. This enterprise will be possible thanks to the team of several different Brazilian groups around this project. We will harness GWAS data already collected and generated by the REDS-II Study, the Bambui Study, and the Heart Institute Heart Failure Cohort Study. In addition, we will generate new large-scale genotype data from the SaMi-Trop Cohort. Taken together, our efforts will result on a more than 10-fold increase in the number of available individuals with Chagas disease that can be analyzed using a GWAS approach. Specifically, we propose to address this problem through the following specific aims: 1. Recruit 1,000 new individuals with the indeterminate form at the Montes Claros, MG region and conduct genome-wide genotyping experiments in 2,000 samples available from the SaMi-Trop cohort, the new indeterminate form group, and approximately 1,000 un-genotyped samples from the Brazilian Consortium for Genetics of Chagas Cardiomyopathy; 2. Conduct a meta-analysis of the different GWAS studies taking part in this initiative; 3. Ascertain and enroll T. cruzi infected individuals from the same nuclear families for the conduct of Chagas cardiomyopathy heritability and future sequencing studies.